PROJECT SUMMARY/ABSTRACT The Hematologic Malignancies Program (HMP) is a multidisciplinary, collaborative group of basic, translational, and clinical investigators that includes 74 members (46 primary, 28 associate) from 11 departments. The HMP is led by Robert Z. Orlowski, a laboratory-based physician-scientist with expertise in plasma cell biology, protein homeostasis, and drug resistance; Michael Andreeff, a laboratory-based physician-scientist focusing on lymphoid and myeloid cell biology, apoptotic signaling, and stem cell biology; and Hagop M. Kantarjian, a clinician-scientist who is an authority on clinical and translational leukemia biology. Members of the HMP pursue the goal of enhancing our understanding of the pathobiology of hematologic malignancies, and leveraging this new knowledge to develop effective personalized, targeted treatment strategies that ultimately will enable us to cure all patients with these diseases. To achieve this goal, the HMP has the following specific aims: Aim 1: To study the epigenome and identify novel drivers of malignant disease and to develop therapies targeted to these features; Aim 2: To develop antibodies, vaccines, and adoptive cellular immunotherapies that boost immune recognition and eliminate malignant cells; Aim 3: To define microenvironmental influences on tumor biology and drug resistance that modulate biomarkers and regulate chemosensitivity; and Aim 4: To validate novel therapies in preclinical models and translate them in a rational, biomarker-driven approach to maximize their impact upon patient outcomes. Program annual direct peer-reviewed funding totals $6.7M, of which $3.8M (57%) is from the National Cancer Institute, including a SPORE in Leukemia. The HMP is leveraging strategic industry alliances and the MD Anderson Moon Shots Program to enhance the breadth of investigator-initiated translational studies and to strengthen understanding of basic biology of these malignancies. Over the last six years, HMP investigators have authored more than 2017 publications where 1126 (56%) represent intra-programmatic collaborations, 545 (27%) represent inter-programmatic collaborations, and 1192 (59%) represent inter- institutional collaborations. Fifty-one percent of publications have appeared in journals with IF >5 and 20% in journals with IF >10, including Cancer Cell, N Engl J Med, and Lancet Oncol. Program members utilized 14 shared resources. During the past grant period, program members contributed significantly to regulatory approval of multiple agents for hematologic malignancies, including small-molecule inhibitors of Bruton tyrosine kinase, BCR/ABL, B-cell CLL/lymphoma 2, and Janus kinase 2 as well as immunotherapies targeting CD19 and other moieties.